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Abstract：
Intra-tumor heterogeneity compromises the clinical value of transcriptomic classifications of colorectal cancer. We investigated the prognostic effect of transcriptomic heterogeneity and the potential for classifications less vulnerable to heterogeneity in a single-hospital series of 1093 tumor samples from 692 patients, including multiregional samples from 98 primary tumors and 35 primary-metastasis sets. We show that intra-tumor heterogeneity of the consensus molecular subtypes (CMS) is frequent and has poor-prognostic associations independently of tumor microenvironment markers. Multiregional transcriptomics uncover cancer cell-intrinsic and low-heterogeneity signals that recapitulate the intrinsic CMSs proposed by single-cell sequencing. Further subclassification identifies congruent CMSs that explain a larger proportion of variation in patient survival than intra-tumor heterogeneity. Plasticity is indicated by discordant intrinsic phenotypes of matched primary and metastatic tumors. We conclude that multiregional sampling reconciles the prognostic power of tumor classifications from single-cell and bulk transcriptomics in the context of intra-tumor heterogeneity, and phenotypic plasticity challenges the reconciliation of primary and metastatic subtypes.
摘要：
肿瘤内异质性损害了结直肠癌转录组分类的临床价值。我们调查了转录组异质性的预后效应，以及在来自692例患者的1093例肿瘤样本的单医院系列中，较不容易受到异质性影响的分类的可能性。包括98个原发性肿瘤和35个原发性转移组的多区域样本。我们表明，共有分子亚型（CMS）的肿瘤内异质性是常见的，并且与肿瘤微环境标志物无关，预后不良。多区域转录组学揭示了癌细胞固有和低异质性信号，这些信号概括了单细胞测序提出的固有CMS。进一步的子分类识别了一致的CMS，这些CMS解释了比肿瘤内异质性更大的患者生存率变化比例。可塑性由匹配的原发性和转移性肿瘤的不一致内在表型指示。我们得出的结论是，在肿瘤内异质性的背景下，多区域采样可以调和来自单细胞和大量转录组学的肿瘤分类的预后能力，和表型可塑性挑战了原发性和转移性亚型的协调。
